KR20140079430A - Transdermal delivery of high viscosity bioactive agents - Google Patents

Abstract

Mechanisms and methods for delivering high viscosity compositions are described. The composition comprises a bioactive agent for delivery to a subject in need of the bioactive agent. The method delivers the bioactive agent to the body's natural defense mechanism with little loss of formulation with high bioavailability. The apparatus includes one or more microneedles having a structure fabricated on the surface of the microneedles to form nano-topography. Composite patterns can be made that contain regular or irregular patterns of structures, such as structures of different sizes and / or shapes.

Description

TECHNICAL FIELD [0001] The present invention relates to a transdermal delivery method for a highly viscous bioactive agent,

Targeted drug delivery that provides a system of a subject with a bioactive agent (e. G., A drug or therapeutic agent) in active and effective concentrations is a long pursued goal. In order to achieve this goal, many difficulties must be overcome. For example, a bioactive agent must first be successfully delivered internally, and the human body has developed many barriers to entry of foreign substances. In addition, the nature of the bioactive agent itself or the concentration of bioactive agent required to achieve the desired effect often results in the formation of a high viscosity composition, which further amplifies the difficulty in successfully passing through the natural barrier of the body.

Current delivery methods used for high viscosity compositions include oral delivery, injection, and infusion. Unfortunately, both of these methods are problematic with respect to the successful delivery of high-viscosity compositions, as well as with objects that accept the composition. For example, although injection may often be used for high viscosity compositions, small gauge needles that require very high pressure over a long period of time for delivery of high viscosity compositions are used. For example, 0.5 milliliters of a 20 centipoise (cP) protein solution can take up to 600 seconds to pass through a 34 gauge needle. Also, given the time required for delivery of a single dose, the injection is painful and the injection can develop scar tissue, given the long-term use of the formulation. Oral delivery requires the successful absorption of the digestive tract through the inner surface of the epithelium as well as the avoidance of degradation of the bioactive agent by the digestive material, and both of these difficulties can be very difficult to overcome. Oral delivery also often results in gastrointestinal disturbances of the subject. Moreover, both injection and oral delivery tend to result in a burst of agent and a greater variation in steady-state delivery than is desirable for system concentration. Infusion therapy can be used to deliver bioactive agents directly to blood vessels, muscles, or subcutis tissues. Transmission through current infusion therapy may be performed using an infusion pump as a relatively steady state delivery to an outpatient or even for a prolonged period of time, but infusion therapy is invasive, increasing the risk of infection at the infusion site, Pumps, percutaneous tubing, and the like.

Transdermal delivery devices have been developed as attempts to provide painless routes for successful delivery of bioactive agents over a sustained period of time. For example, transdermal patches have been found to be useful in providing a system of a subject with a bioactive agent such as nicotine, scopolamine, estrogen, nitroglycerin, and the like. To achieve success, the transcutaneous strategy must deliver the formulation across the epidermis that has evolved to have the primary function of dispelling foreign substances. The stratum corneum, the outermost layer of the epidermis, has structural stability provided by superficial keratinocytes and bridging keratin fibers that are joined together by keratinocytes and embedded within the lipid matrix, all of which provide excellent barrier function. Below the stratum corneum is a granular layer, in which tight junctions are formed between keratinocytes. Adherent synapses may include a number of plaque proteins (e. G., ZO-1, ZO-2, ZO-3, neuron, etc.) as well as networks of buried epidermal proteins (e. G., Claudin, 0.0 > simpleleak). ≪ / RTI > Adherent synapses are found in the granules of the skin as well as the inner epithelium and endothelium (eg, intestinal epithelium, blood-brain barrier, vascular wall). Underneath both the stratum corneum and the granular layer is the anolyte. The anolyte layer comprises Langerhans cells, which are dendritic cells that can become immune and / or foreign to the invading agent by becoming antigen-delivering cells that perform well.

It helped break the initial barrier in the dermis by adding a micro needle on the transdermal delivery device, such as a patch. Unfortunately, despite the above improvements, transdermal delivery devices are currently limited only to the delivery of low-viscosity compositions, particularly low-molecular weight formulations that are not charged with suitable lipophilic properties. Moreover, even if successful over natural boundaries, there is still a problem with maintaining the active level of the delivered formulation and avoiding foreign and immune responses.

There is a need in the art for mechanisms and methods for delivering bioactive agents. More specifically, there is a need for mechanisms and methods that are capable of successfully delivering a highly viscous composition comprising a bioactive agent and preventing the targeting of the bioactive agent by the body's own defense mechanisms.

SUMMARY OF THE INVENTION [

According to one embodiment, a mechanism for delivering a composition across a skin barrier is disclosed. More specifically, the instrument may comprise a plurality of nanostructures fabricated on the micro needle and its surface. The nanostructures can be arranged in a predetermined pattern. The device also includes a composition in fluid communication with the micro needle. More specifically, the composition comprises a bioactive agent and may have a viscosity of greater than about 5 centipoise.

According to yet another embodiment, a method for delivering a composition to a subject is disclosed. The method includes penetrating the stratum corneum of a subject using a microneedle in fluid communication with the composition. The composition comprises a bioactive agent and has a viscosity of greater than about 5 centipoise. In addition, the micro needle includes a plurality of nanostructures forming a pattern formed on its surface. The method also includes delivering the bioactive agent through the micro needle at a rate of about 0.4 mg / hr / cm < 2 > based on the surface area of the micro needle.

A sufficient and possible disclosure of the subject matter of the patent, including the best mode of the subject matter to be covered by the ordinary skilled artisan in the field, will be more particularly described with reference to the accompanying drawings in the remainder of the specification.
Figure 1 shows one embodiment of a micro needle instrument.
Figure 2 shows another embodiment of a microneedle mechanism.
Figure 3 illustrates one embodiment of a micro needle that includes a surface that defines nanotopography capable of interacting with an extracellular matrix (ECM).
Figure 4 illustrates one embodiment of a composite pattern that may be formed on a micro needle surface.
Figure 5 shows a pattern comprising multiple repetitions of the composite pattern of Figure 4;
Figure 6 shows a Sierpinski triangle fractal.
Figures 7a-7d illustrate complex fractal and fractal-like nano topography.
Figure 8 shows another composite pattern that may be formed on the micro needle surface.
FIG. 9 is an illustrative example of a nano-sized structure as may be used for nano-sized structures as described herein, including a square packing design (FIG. 9A), a hexagonal packing design (FIG. 9B) Packing density is shown.
10A-10C schematically illustrate a nanoimprinting method as may be used in the formation of a device in one embodiment.
11 schematically illustrates one embodiment of the apparatus including the release liner (FIG. 11A) and one embodiment of the apparatus in which the release liner is subsequently removed (FIG. 11B).
Figure 12 is a perspective view of one embodiment of a transdermal patch prior to delivery of the drug compound.
13 is a front view of the patch of Fig.
14 is a perspective view of the patch of FIG. 12 with the release member partially removed from the patch.
15 is a front view of the patch of Fig.
Fig. 16 is a perspective view of the dermal patch of Fig. 12 in use after removal of the release member;
17 is a front view of the patch of Fig.
Figure 18 is a perspective view of another embodiment of a transdermal patch prior to delivery of the drug compound.
19 is a front view of the patch of Fig. 18;
20 is a perspective view of the patch of FIG. 18 with the release member partially stripped from the patch.
21 is a front view of the patch of Fig.
22 is a perspective view of the patch of FIG. 18 with the release member completely stripped from the patch.
Fig. 23 is a perspective view of the dermal patch of Fig. 18 for use after removal of the release member. Fig.
Figures 24A-24E illustrate a number of nano topography patterns as described herein.
25 is a SEM of a film comprising a nanopatterned surface.
Figures 26a and 26b are two SEMs of a film comprising another nanopatterned surface.
Figure 27 is an SEM of a film comprising another nanopatterned surface.
Figure 28 is an SEM of a film comprising another nanopatterned surface.
29 is an SEM of a film comprising another nanopatterned surface.
30 is an SEM of a film comprising another nanopatterned surface.
31 is an SEM of a film comprising another nanopatterned surface.
32 is a SEM of a film comprising another nanopatterned surface.
33 is an SEM of a film comprising another nanopatterned surface.
34A-34D are images of a microneedle array as described herein with a high magnification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [

Various embodiments of the disclosed subject matter will now be described in detail, and one or more examples thereof are described below. Each example is provided by way of illustration and not limitation. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or concept of the patent subject matter. For example, embodiments illustrated or described as part of one embodiment can be used in another embodiment to obtain additional embodiments. Accordingly, the present disclosure intends to include such modifications and variations as fall within the scope of the appended claims and their equivalents.

An apparatus and method for providing a route for delivering a composition comprising a bioactive agent over a skin barrier of a subject is described herein, wherein the transdermal delivery device comprises one or more microneedles. More specifically, the composition may have a viscosity that is not considered deliverable by use of a high viscosity, especially in the past by the use of a transdermal device, for example, a viscosity of greater than about 5 centipoise. The method may include delivering the high viscosity bioactive agent to the subject at a useful rate, for example, at a rate of greater than about 5 mg / ml per hour. The high viscosity of the composition may be due, for example, to a high concentration of the bioactive agent in the composition, a high molecular weight bioactive agent in the composition, a high molecular weight or high concentration in the composition, or a combination of factors. For example, the composition may comprise one or more high molecular weight bioactive agents, such as protein therapeutics having a molecular weight of greater than about 100 kDa. In the past, achieving transdermal delivery of the bioactive agent has proved difficult or impossible, due to the inability to break through the natural barriers of the body.

A subject that may benefit from the method may comprise any animal subject in need of delivery of the bioactive agent. For example, the subject can be a human or any other mammal or animal that can benefit from the delivery method.

The delivery method uses a transdermal delivery device comprising a pattern of structures constructed on the surface of one or more micro needles and one or more micro needles. Also, at least a portion of the structure fabricated on the surface of the microneedles is fabricated on a nanometer scale. The term "fabricated " as used herein generally refers to a feature that is not specifically identified with a surface feature that is specifically designed, manipulated and / or manufactured to be present on the surface of the micro needle, Structure. Thus, the transdermal delivery device will include a predetermined pattern of nanostructures, i.e., nanotopography, on the surface of the micro needle.

Without wishing to be bound by any particular theory, it is believed that through interaction between the nanotopography on the surface of the micro needle and the surrounding biological material or structure, the micro needle is immobilized on the membrane potential, membrane protein, and / It is believed that it is possible to regulate and / or modulate intercellular synapses (e.g., tight junctions, gap junctions, and / or desmosomes) between cells and between cells. More specifically, it is believed that the interaction between the nanotopography of the micro needle and the surrounding biological material can rearrange the epithelial adhesion association of the dermal tissue and temporarily enhance the porosity of the local barrier structure. The delivery of a highly viscous composition comprising a bioactive agent, which also exceeds the skin barrier, can be facilitated.

It is also believed that the interaction between the nanotopography of the device and the surrounding biological structures can facilitate delivery of the composition comprising the bioactive agent through systemic delivery across skin barriers and other natural boundaries. Specifically, through the use of nanostructured transdermal delivery devices, permeability is enhanced not only in tissue within adjacent contact areas of the device but also in surrounding tissue. Not only does enhanced permeability occur between cells in contact with the microneedles, but this effect is also believed to be able to disrupt other cells in the area, including cells of different tissue types. It can be interpreted that the enhanced porosity effect is on the nearby structures and tissue types and thus the porosity of nearby vasculature structures can be enhanced.

The interaction between the device and the contact tissue leads to a rearrangement of the epithelial adhesion junctions of the dermal tissue and thus a cascade reaction in which a similar effect is delivered to cells of the local blood vessels, for example, cells of both the basement membrane and the endothelium of the local capillary ≪ / RTI > This may result in perforation of the capillary wall, allowing the bioactive agent to enter the cardiovascular system directly. Whereby the absorption of the bioactive agent by the system of the subject can be significantly enhanced.

 By the use of a device, delivery of a high viscosity composition comprising one or more bioactive agents can be improved. The high viscosity composition may have a viscosity of, for example, greater than about 5 centipoise, greater than about 10 centipoise, or greater than about 25 centipoise. In one embodiment, the composition may have a viscosity of from about 10 centipoise to about 50 centipoise, for example, from about 30 centipoise to about 40 centipoise.

The viscosity of the composition can be determined according to standard operations. For example, one method of measuring viscosity requires inserting a piston into a closed vessel containing the sample fluid and then measuring the torque required to rotate the piston in the vessel. This method is suitable for measuring the viscosity of a larger fluid sample, but it has the disadvantage of requiring and consuming a comparatively large volume of sample fluid. The volume may not be available in the assay, especially in the case of biological assays.

According to an alternative method, the viscosity can be determined using the diffusion of markers (i.e., fluorescently labeled beads or macromolecules) with a known size and spreading factor across the microfluidic free interface formed in the composition. This technique is applicable to the analysis of the viscosity of biological or physiological samples because the size of the microfluidic channel where diffusion occurs occupies a relatively small volume.

The viscosity of the composition can be determined using a standard instrument, for example, a capillary viscometer as is known in the art. Exemplary rheometers that may be used include, but are not limited to, Brookfield ™ programmable rheometers, LV-DV-III, Ostwald viscosity meters, VROC® viscometer, a micrometer scale viscosity sensor chip for small samples But are not limited to, a viscometer rheometer-on-a-chip, a Haake Viscotester VT 550 rheometer, and the like.

The device can deliver the high viscosity composition at a useful rate to a subject in need of a high viscosity composition. For example, the high viscosity composition may have a viscosity of greater than about 0.4 mg / hr / cm2, greater than about 1 mg / hr / cm2, greater than about 3 mg / hr / cm2, or greater than about 6 mg / hr / / RTI > < RTI ID = 0.0 >

There are no particular limitations on bioactive agents as can be delivered by the use of the above methods. Biologically active agents may include natural or synthetic agents, small molecule agents, and the like. In one embodiment, a high molecular weight bioactive agent (e. G., A non-human antibody that confers molecular weights greater than about 400 Da, greater than about 10 kDa, greater than about 20 kDa, or greater than about 100 kDa, Protein synthesis or a natural bioactive agent).

In one particular example, the bioactive agent delivered in accordance with the method may be a high molecular weight protein therapeutics. The term "protein therapeutic agent" as used herein refers to any biologically active proteinaceous compound, including but not limited to natural, synthetic, and recombinant compounds, fusion proteins, chimeras, etc., as well as 20 standard amino acids and / ≪ / RTI > or synthetic amino acids. For example, protein therapeutics having a molecular weight of greater than about 100 kDa, or greater than about 125 kDa, such as from about 125 kDa to about 200 kDa, or from about 150 kDa to about 200 kDa, .

In one embodiment, the methods and apparatus can be used to deliver a composition comprising a high concentration of a bioactive agent in the form of a high molecular weight bioactive agent or a small molecule bioactive agent. For example, the composition may contain more than about 5 mg / ml, greater than about 10 mg / ml, greater than about 30 mg / ml, greater than about 50 mg / ml, greater than about 100 mg / Ml. ≪ / RTI > For example, the composition may comprise a bioactive agent at a concentration of from about 35 mg / ml to about 500 mg / ml, or from about 50 mg / ml to about 400 mg / ml.

Agents include proteinaceous agents such as insulin, immunoglobulins (e.g., lgG, lgM, lgA, lgE), TNF-a, antiviral agents and the like; Polynucleotide preparations including plasmids, siRNA, RNAi, nucleoside anticancer agents, vaccines and the like; And small molecule preparations such as alkaloids, glycosides, phenols, and the like. Agents may include anti-infective agents, hormones, drugs that regulate cardiac activity or blood flow, pain control agents, and the like. Other substances that may be delivered according to the disclosure are those useful for the prevention, diagnosis, alleviation, treatment, or cure of disease. A non-limiting list of agents includes, but is not limited to, angiogenesis inhibitors, antidepressants, antidiabetic agents, antihistamines, antiinflammatory agents, butorphanols, calcitonins and analogues, COX-II inhibitors, dermatological agents, dopamine agonists and antagonists, Growth hormones and analogs (including growth hormone releasing hormone), growth hormone antagonists, heparin, hirudin and hirudin analogs such as hiruoguide, IgE < RTI ID = 0.0 > Inhibitors and other protein inhibitors, immunosuppressants, insulins, insulinotropins and analogs, interferons, interleukins, luteinizing hormones, luteinizing hormone releasing hormones and analogs, monoclonal or polyclonal antibodies, nausea, muscle relaxants, narcotic analgesics , Nicotine, non-steroidal anti-inflammatory agents, oligosaccharides, parathyroid hormone and analogs, Vasodilators, including, but not limited to, hormone antagonists, prostaglandin antagonists, prostaglandins, scopolamine, sedatives, serotonin agonists and antagonists, sexual dysfunction, tissue plasminogen activator, For example, tuberculin and other hypersensitizers, which are described in U.S. Patent No. 6,569,143, entitled " Method of Intradermally Injecting Substances, "whose title is incorporated herein by reference in its entirety have. Vaccine combinations may include antigenic or antigenic compositions capable of eliciting an immune response against human pathogens or from other viral pathogens.

In one embodiment, the method can be used to deliver a steady flow of formulation to a subject in need thereof, in the treatment of chronic conditions, such as rheumatoid arthritis. RA drugs that may be delivered may include anti-inflammatory drugs, including symptom-suppressing compounds such as analgesics and steroidal and non-steroidal anti-inflammatory drugs (NSAIDs), as well as disease-modifying anti-rheumatic drugs (DMARDs).

The RA drug may include, but is not limited to, one or more analgesics, anti-inflammatory drugs, DMARDs, herbal-based drugs, and combinations thereof. It is understood that the specific compounds may belong to one or more of the general categories described herein. For example, many compounds can function as both analgesics and anti-inflammatory agents; Herbal-based drugs can also function as anti-inflammatory agents as well as DMARDs. Moreover, a large number of compounds that can belong to a single category can be delivered. For example, the method can be used to deliver a number of analgesics such as acetaminophen and codeine, acetaminophen and hydrocodone (vicodin), and the like.

The composition may comprise one or more bioactive agents together with other ingredients as are generally known in the art. For example, the composition may comprise one or more pharmaceutically acceptable excipients. The term "excipient " as used herein generally refers to a bioactive agent delivered to a subject in order to improve one or more properties, such as the handling or storage properties of the bioactive agent, Refers to any material used in conjunction with the active ingredient (s), which is not itself a bioactive agent. The excipient may be, but is not limited to, a solvent (e.g., a lower alcohol such as ethanol or isopropanol; or water), a penetration enhancer, a thickener, a wetting agent, a lubricant, a softener, an unpleasant odor, A substance to be added, an aromatic substance, an azide, and a substance added to improve the appearance or texture of the composition or delivery apparatus. Any of these excipients may be used in any amount as generally known.

Penetration enhancers non-limiting examples C ₈ -C ₂₂ fatty acids such as isostearic acid, octanoic acid, and oleic acid; C ₈ -C ₂₂ fatty alcohols such as oleyl alcohol and lauryl alcohol; C ₈ -C ₂₂ fatty acid lower alkyl esters, such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; Di (lower) alkyl esters of C ₆ -C ₂₂ diacids such as diisopropyl adipate; Monoglycerides, such as glyceryl monolaurate of C ₈ -C ₂₂ fatty acids; Tetrahydrofurfuryl alcohol polyethylene glycol ether; Polyethylene glycol, propylene glycol; 2- (2-ethoxyethoxy) ethanol; Diethylene glycol monomethyl ether; Alkyl aryl ethers of polyethylene oxide; Polyethylene oxide monomethyl ether; Polyethylene oxide dimethyl ether; Dimethyl sulfoxide; Glycerol; Ethyl acetate; Acetoacetic acid esters; N-alkylpyrrolidone; And terpenes. Additional penetration enhancers suitable for use may be found in US Published Patent Application 2002/0111377, which is incorporated herein by reference. The one or more penetration enhancers, if present, can be present in a total amount of from about 0.01% to about 25%, or from about 0.1% to about 15%, of the composition, generally on a weight basis.

Thickening agents (also referred to herein as gellants) include anionic polymers such as polyacrylic acid (Carbopol® from Noveon, Inc. of Cleveland, Ohio), carboxypolymethylene, carboxymethylcellulose Such as Carbopol® Ultrez® 10, Carbopol® 940, Carbopol® 941, Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol®, ® ETD 2001, Carbopol® EZ-2 and Carbopol® EZ-3, and other polymers such as Pemulen® polymeric emulsifiers, and Noveon® polycarbophil. The thickening agent, if present, may generally be present in a total amount of from about 0.1% to about 15%, from about 0.25% to about 10%, or from about 0.5% to about 5% by weight.

Additional thickeners, enhancers and adjuvants are generally described in Remington's The Science and Practice of Pharmacy as well as in the Handbook f Pharmaceutical Excipients, Arthur H. Kibbe ed. 2000].

One or more neutralizing agents may be present to assist in the formation of the gel. Suitable neutralizing agents include, but are not limited to, sodium hydroxide (for example as an aqueous mixture), potassium hydroxide (for example as an aqueous mixture), ammonium hydroxide (for example as an aqueous mixture), triethanolamine, tromethamine 2-hydroxymethyl-1,3-propanediol), aminomethyl propanol (AMP), tetrahydroxypropylethylenediamine, diisopropanolamine, Ethomeen C-25 (Armac Industrial Division) (Ethylhexyl) amine (BASF-Wyandotte Corp., Intermediate Chemicals Division), triamylamine, Jeffamine D-1000 (Jefferson- (American Cyanamid Co.), Armeen CD (Armeen CD) (Arum Industrial Division), ALMIN 7D (Armeen < RTI ID = 0.0 > (Alamine 7D) (Henkel Cooper The neutralizing agent may be present in an amount sufficient to form a gel suitable for contacting the skin of a mammal, such as not more than about 10% (by weight) of the composition , For example from about 0.1% to about 5% by weight of the composition.

The composition may include one or more pharmaceutically acceptable wetting agents (also referred to as surfactants) as excipients. Non-limiting examples of surfactants include quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ether, e.g., (Polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils such as polyoxyethylene (8) caprylic acid (8), polyoxyethylene Rick / capric mono- and diglycerides (e.g. Labrasol (TM) from Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; Polyoxyethylene alkyl ethers such as polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters such as polysorbates (For example, Tween 80 of ICI), propylene glycol fatty acid esters such as propylene glycol laurate (e.g., lauroglycol ( Lauroglycol ™), sodium lauryl sulfate, fatty acids and salts thereof such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate, sorbitan esters such as, for example, Sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tylox ≪ / RTI > and mixtures thereof. The one or more wetting agents, when present, generally together comprise from about 0.25% to about 15%, from about 0.4% to about 10%, or from about 0.5% to about 5% of the total weight of the composition.

The composition may include one or more pharmaceutically acceptable lubricants (including anti-adhesion and / or lubricants) as excipients. Suitable lubricants include glyceryl beaufate (e.g., Compritol (TM) 888); Stearic acid and its salts including magnesium stearate (magnesium stearate), calcium stearate and sodium stearate; Hydrogenated vegetable oils (e.g., Sterotex (TM)); Colloidal silica; talc; Wax; Boric acid; Sodium benzoate; Sodium acetate; Sodium fumarate; Sodium chloride; DL-leucine; PEG (e.g., Carbowax ™ 4000 and Carbowax ™ 6000); Sodium oleate; Sodium lauryl sulfate; ≪ / RTI > and magnesium lauryl sulfate. The lubricant, when present, can generally comprise from about 0.1% to about 10%, from about 0.2% to about 8%, or from about 0.25% to about 5% of the total weight of the composition.

The composition may comprise one or more softening agents. Exemplary softeners include mineral oil, a mixture of mineral oil and lanolin alcohol, cetyl alcohol, cetostearyl alcohol, vaseline, vaseline and lanolin alcohol, cetyl ester wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, iso But are not limited to, propyl palmitate, propyl palmitate, lecithin, allyl caproate, alteoopinicinis extract, arachidyl alcohol, Argo base EUC, butylene glycol dicaprylate / dicaprate, acacia, allantoin, carrageenan, cetyl dimethicone, Diethyl succinate, diheptyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, isoamyl laurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnut oil , Wheat germ oil, highly refined almonds, highly refined sesame, highly refined base , Octyl palmitate, a car including ruffled Rick / capric triglyceride and glyceryl cocoate, but not intended to be limited only this. The composition may include one or more softeners in a total amount of from about 1% to about 30%, from about 3% to about 25%, or from about 5% to about 15% of the composition by weight.

The composition may comprise one or more antimicrobial preservatives. Exemplary antimicrobial preservatives include benzoic acid, phenolic acid, sorbic acid, alcohol, benzethonium chloride, bronopole, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidourea, Methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium propionate, or thimerosal But is not limited to. The one or more antimicrobial preservatives, if present, may be present in a total amount of from about 0.1% to about 5%, from about 0.2% to about 3%, or from about 0.3% to about 2% of the composition, generally by weight .

The composition may comprise one or more emulsifying agents. The term "emulsifying agent " as used herein generally refers to an agent capable of reducing the surface tension between a nonpolar phase and a polar phase, and includes a compound defined as a" self-emulsifying "agent. Suitable emulsions can be derived from any class of pharmaceutically acceptable emulsions, including carbohydrates, proteins, high molecular weight alcohols, wetting agents, waxes and finely divided solids. The one or more emulsifying agents, if present, can comprise from about 1% to about 15%, from about 1% to about 12%, from about 1% to about 10%, or from about 1% to about 5% By weight of the composition.

The compositions may be prepared by any technique known to one of ordinary skill in the art of pharmacy, pharmacology, drug delivery, pharmacokinetics, medical or other related fields, including mixing the one or more excipients with a therapeutic agent to form a composition, .

Transcutaneous delivery devices can be made from a variety of materials including metals, ceramics, semiconductors, organic materials, polymers, as well as their composites. For example, pharmaceutical grades of stainless steel, titanium, nickel, iron, gold, tin, chromium, copper, alloys of these or other metals, silicon, silicon dioxide, and polymers may be used. Typically, the device is formed of a biocompatible material that can have a pattern of the structure as described herein on the surface. The term "biocompatibility" generally refers to a material that does not substantially adversely affect cells or tissues in the area to which the device is delivered. The material also has no substantially medically undesirable effect on any other area of the living subject. The biocompatible material may be a synthetic or natural material. Some examples of suitable biocompatible materials that are also biodegradable include polymers of hydroxy acids such as lactic acid and glycolic acid, polylactide, polyglycolide, polylactide-co-glycolide, copolymer with polyethylene glycol, polyanhydrides, Include poly (ortho) esters, polyurethanes, poly (butyric acid), poly (valeric acid), and poly (lactide-co-caprolactone). Other suitable materials may include, but are not limited to, polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, and polyesters. The device may also be essentially nonporous or porous and may be uniform or non-uniform throughout the device in terms of material, geometry, robustness, etc., and may have a fixed or semi-fixed shape of rigidity.

Fig. 1 shows a typical micro needle transcutaneous delivery device 10. As can be seen, the instrument comprises an array of individual needles 12; These are sized and shaped to penetrate biological barriers without breaking each individual micro needle. The microneedles may be hollow, porous, or hollow as in Fig. The micro needle can include an annular bore that can extend through all or a portion of the needle, e.g., extending parallel to the direction of the needle or, if desired, on either side of the needle have. For example, Figure 2 shows an array of microneedles 14, each including channels 16 on one side of the needle, such as may be used to deliver a formulation to a subcutaneous location, for example. For example, the channel 16 may be at least partially aligned with the opening of the base 15 to form a junction between the opening and the channel 16, allowing passage of the material through the channel 16.

When the channel 16 is present, its dimensions may be selected to specifically induce capillary flow of the composition comprising the bioactive agent. Capillary flow generally occurs when the fluid's adhesion to the walls of the channel is greater than the cohesive force between the liquid molecules. Specifically, the capillary pressure is inversely proportional to the cross-sectional dimension of the channel 16 and is directly proportional to the surface tension of the liquid multiplied by the cosine of the contact angle of the fluid in contact with the channel forming material. Thus, in order to facilitate capillary flow in the patch, the cross-sectional dimensions (e.g., width, diameter, etc.) of the channels 16 can be selectively adjusted, and smaller dimensions generally result in larger capillary pressures do. For example, in some embodiments, the cross-sectional dimensions of the channel are typically from about 1 micrometer to about 100 micrometers, in some embodiments from about 5 micrometers to about 50 micrometers, in some embodiments from about 10 micrometers to about 10 micrometers 30 micrometers. The dimensions may be constant or may vary as a function of the length of the channel 16. The length of the channel may vary for different volumes, flow rates, and residence times for drug compounds. For example, the length of the channel may be from about 10 micrometers to about 800 micrometers, in some embodiments from about 50 micrometers to about 500 micrometers, and in some embodiments from about 100 micrometers to about 300 micrometers. The cross-sectional area of the channel may also vary. For example, the cross-sectional area may be from about 50 square micrometers to about 1,000 square micrometers, in some embodiments from about 100 square micrometers to about 500 square micrometers, in some embodiments from about 150 square micrometers to about 350 square micrometers Lt; / RTI > In addition, the aspect ratio (length / cross-sectional dimension) of the channel may range from about 1 to about 50, in some embodiments from about 5 to about 40, and in some embodiments from about 10 to about 20. If the cross-sectional dimension (e.g., width, diameter, etc.) and / or length varies as a function of length, the aspect ratio can be determined from the average dimension.

It should be understood that the number of microneedles shown in the figures is for illustrative purposes only. The actual number of micro needles used in the micro needle assembly may range, for example, from about 500 to about 10,000, in some embodiments from about 2,000 to about 8,000, and in some embodiments from about 4,000 to about 6,000.

The individual microneedles may have straight or tapered shafts. In one embodiment, the diameter of the microneedles is maximum at the basal end of the microneedles and can be tapered to some point at the end of the circle from the base. The microneedles may be made with a shaft comprising both a straight (non-tapered) portion and a tapered portion.

The microneedles may be formed with a shaft having a circular or non-circular cross-section. For example, the cross-section of the microneedles may be polygonal (e.g., astragaliform, square, triangular), rectangular, or any other shape. The shaft may have one or more bores and / or channels.

The size of the individual needles can be optimized according to the desired targeting depth, the strength requirements of the needle to avoid breakage in a particular tissue type, and the like. For example, the cross-sectional dimensions of the transdermal micro needle can be from about 10 nanometers (nm) to 1 millimeter (mm), or about 1 micrometer (m) to about 200 micrometers, or about 10 micrometers to about 100 micrometers Lt; / RTI > The outer diameter may be from about 10 micrometers to about 100 micrometers and the inner diameter of the hollow needle may be from about 3 micrometers to about 80 micrometers. The leading edge typically has a radius of about 1 micrometer or less.

The length of the microneedles will generally vary depending on the desired application. For example, the microneedles may be about 1 micrometer to about 1 millimeter in length, for example about 500 micrometers or less, or about 10 micrometers to about 500 micrometers, or about 30 micrometers to about 200 micrometers have.

The arrays of microneedles need not all include the same microneedles. The array can include a mix of microneedles having various lengths, diameters, diameters, cross-sectional shapes, nanostructured surfaces, and / or spacing between microneedles. For example, the microneedles may be spaced apart in a uniform manner, such as in a rectangular or square grid or concentric circles. The spacing may vary depending on a number of factors, including the height and width of the microneedles, as well as the amount and type of any material that is to be moved through the microneedles. While a variety of arrangements of microneedles are useful, particularly useful microneedle arrangements are those in which the "tip-to-tip" spacing between microneedles is greater than about 50 microns, and in some embodiments, between about 100 and about 800 microns Meter, and in some embodiments from about 200 to about 600 micrometers.

Referring back to Fig. 1, the microneedles may be fixed (i.e., attached to or integrated with the substrate) so that they are oriented perpendicularly or at an angle to the substrate. In one embodiment, the microneedles can be oriented perpendicularly to the substrate and microneedles of greater density per unit area of substrate can be provided. However, the array of microneedles may include microneedle orientation, height, material, or a mixture of other parameters. Substrate 20 may be made from a rigid or flexible sheet of metal, ceramic, plastic or other material. The substrate 20 may be as thin as about 1000 micrometers or less in thickness, from about 1 to about 500 micrometers in some embodiments, and from about 10 to about 200 micrometers in some embodiments to meet the needs of the instrument .

The micro needle surface may define nano topography thereon in an irregular or regular pattern. Figure 3 schematically shows the ends of two representative microneedles 22. The micro needle 22 defines a central bore 24 as can be used for delivery of the formulation through the micro needle 22. The surface 25 of the micro needle 22 defines the nano topography 26. In this particular embodiment, the nanotapography 26 defines an irregular pattern on the surface 25 of the micro needle 22.

The micro-needles may comprise a number of identical structures formed on a surface, or may comprise different structures formed in various sizes, shapes, and combinations thereof. The predetermined pattern of the structure may include a mix of structures having various lengths, diameters, cross-sectional shapes, and / or gaps between the structures. For example, the structure may be spaced apart in a uniform manner, such as in a rectangular or square grid or concentric circles. In one embodiment, the structure may vary in size and / or shape and may form complex nano topography. For example, complex nano topography can define fractal or fractal-like geometry.

The term "fractal " as used herein generally refers to a material that is fragmented at all measurement scales between a maximum scale and a minimum scale so that a particular mathematical or physical property of the structure behaves as if the dimension of the structure is greater than the spatial dimension. Geometric < / RTI > or physical structure having a shape. The mathematical or physical properties of interest may include, for example, the perimeter of the bend or the flow rate in a porous medium. The geometric shape of the fractal can be broken down into portions that define self-similarity, respectively. Fractals are also cyclically defined and have arbitrarily small scale microstructure.

The term "fractal-like" as used herein generally refers to a geometric or physical structure that has one or more of the characteristics of the fractal but not all. For example, a fractal-like structure may include geometric shapes including self-similar portions, but may not include any small scale microstructure. In another example, a fractal-like geometric shape or a physical structure may have an increase (or increase) between cyclic iterations of the geometric shape of the pattern, although the scale may not be uniformly reduced Or decrease. Fractal-like patterns can be simpler than fractal. For example, it can be regular and relatively easily described in the traditional Euclidean geometry language, but fractal may not.

The microneedle surfaces defining the complex nano topography may include structures (e.g., pillars) of the same general shape, and the pillars may be formed with different measurement scales (e.g., nano-scale Filler as well as micro-scale filler). In another embodiment, the microneedles may include structures on the surface that are formed in the same nano-scale with different or different shapes and sizes. In addition, the structure may be formed with a regular array or an irregular distribution. In general, at least a portion of the structure may have a nano-sized (e.g., about 1, 2, 3, 4, 5, Scale nanostructure. The cross-sectional dimension of the nanostructure may generally be greater than about 5 nanometers, such as greater than about 10 nanometers, or greater than about 20 nanometers. For example, the nanostructure may define a cross-sectional dimension of about 5 nanometers to about 500 nanometers, about 20 nanometers to about 400 nanometers, or about 100 nanometers to about 300 nanometers. In the case where the cross-sectional dimension of the nanostructure varies as a function of the height of the nanostructure, the cross-sectional dimension may be an average from the base to the tip of the nanostructure, or the maximum cross-sectional dimension of the structure, e.g. the base of the cone-shaped nanostructure As a cross-sectional dimension.

Figure 4 shows one embodiment of a composite nano topography as may be formed on a surface. This particular pattern includes a large filler 100 at the center and a smaller size peripheral filler 102, 104 provided in a regular pattern. As can be appreciated, this pattern includes repetitions of pillars, each of which is formed to have the same general shape, but may differ in relation to the horizontal dimension. This particular composite pattern is an example of a fractal-like pattern that does not contain the same change of scale between successive cyclic iterations. For example, the filler 102 is a first nanostructure that defines a horizontal dimension that is about one third of the horizontal dimension of a larger filler 100 that is a microstructure, while the filler 104 is a filler 102, Which is about one half of the horizontal dimension of the first nanostructure.

A pattern comprising structures of different sizes may include larger structures with cross-sectional dimensions formed with larger scales, such as microstructures with cross-sectional dimensions greater than about 500 nanometers, with smaller nanostructures. In one embodiment, the microstructures of the composite nanotopography can have a cross-sectional dimension of from about 500 nanometers to about 10 micrometers, from about 600 nanometers to about 1.5 micrometers, or from about 650 nanometers to about 1.2 micrometers . For example, the composite nano topography of FIG. 4 includes a micro-sized filler 100 having a cross-sectional dimension of about 1.2 micrometers.

If the pattern comprises one or more larger microstructures having, for example, an average cross-sectional dimension of the structure or a cross-sectional dimension of greater than about 500 nanometers, determined as the maximum cross-sectional dimension of the structure, the composite nano- For example, a first nanostructure, a second nanostructure, etc. of different sizes and / or shapes. For example, the filler 102 of the composite nano topography of FIG. 4 has a cross-sectional dimension of about 400 nanometers and the filler 104 has a cross-sectional dimension of about 200 nanometers.

Nano topography can be formed of any number of different elements. For example, a pattern of elements may include two different elements, three different elements (an example of which is shown in FIG. 4), four or more different elements. The relative repetition rate of each different element may also vary. In one embodiment, the smallest element of the pattern will be present in greater numbers than the larger element. For example, in the pattern of FIG. 4, there are eight pillars 104 for each filler 102, and eight pillars 102 for a large filler 100 at the center. The larger the size of the element, the less generally the element can be repeated in nano topography. For example, a first element having a cross-sectional dimension that is about 0.5 times the cross-sectional dimension of a larger second element, for example, about 0.3 to about 0.7 times, may be present at about five times or more of the second element in the topography. The first element having a cross-sectional dimension that is about 0.25 times the cross-sectional dimension of the larger second element, or about 0.15 times to about 0.3 times, may be present at about 10 times or more of the second element in the topography.

The spacing of individual elements may also vary. For example, the center-to-center spacing of individual structures may be from about 50 nanometers to about 1 micrometer, for example from about 100 nanometers to about 500 nanometers. For example, the center-to-center spacing between structures may be a nano-sized scale. For example, considering the spacing of nano-sized structures, the center-to-center spacing of structures may be less than about 500 nanometers. However, this is not a prerequisite for topography, and individual structures may be farther apart. The center-to-center spacing of structures can vary depending on the size of the structure. For example, the ratio of the average cross-sectional dimension of two adjacent structures to the center-to-center spacing between these two structures may be about 1: 1 (e.g., contacted) to about 1: 4, 1: 3.5, or about 1: 2 to about 1: 3. For example, the center-to-center spacing can be about twice the average cross-sectional dimension of two adjacent structures. In one embodiment, two adjacent structures each having a cross-sectional dimension of about 200 nanometers may have a center-to-center spacing of about 400 nanometers. Thus, in this case, the ratio of the mean diameter to the center spacing is 1: 2.

The structure spacing can be the same, i. E. Equidistant, or can vary from structure to pattern. For example, the smallest structure of the pattern can be spaced apart by a first distance, and the spacing between the smallest structure and the larger structure of the pattern, or the spacing between the two larger structures of the pattern, May be the same or different.

For example, in the pattern of FIG. 4, the smallest structure 104 has a center-to-center spacing of about 200 nanometers. The distance between the larger filler 102 and each surrounding pillar 104 is less than about 100 nanometers. The distance between the largest filler 100 and each surrounding pillar 104 is also about 100 nanometers smaller than the center-to-center spacing between the smallest pillars 104. Of course, this is not a prerequisite, so all structures may be equidistant or at any arbitrary distance. In one embodiment, the different structures may contact one another on top of each other, or may contact each other adjacent to each other, for example, as discussed further below.

The structures of one topography may all be formed with the same height, generally from about 10 nanometers to about 1 micrometer, but this is not a requirement, and individual structures of one pattern may have one, two or three dimensions And may vary in size. In one embodiment, some or all of the structures of one topography are less than about 20 microns, less than about 10 microns, or less than about 1 micron, such as less than about 750 nanometers, less than about 680 nanometers , Or less than about 500 nanometers. For example, the structure may have a height of about 50 nanometers to about 20 micrometers or about 100 nanometers to about 700 nanometers. For example, it should be understood that a nanostructure or microstructure may have a height that can have a nano-sized cross-sectional dimension and that can be measured at a micro-sized scale, for example, a height of greater than about 500 nm, The structure may have a height of from about 20 nm to about 500 nm, from about 30 nm to about 300 nm, or from about 100 nm to about 200 nm. The micro-sized structure may have a height that is the same as or different from the height of the nano-sized structure of the same pattern. For example, the micro-sized structure may have a height of about 500 nanometers to about 20 micrometers, or in another embodiment about 1 micrometer to about 10 micrometers. The micro-sized structure may also have a micro-scale cross-sectional dimension of greater than about 500 nm, and may have a height of a nano-scale scale of less than about 500 nm.

The aspect ratio (ratio of the height of the structure to the cross-sectional dimension of the structure) of the structure may be from about 0.15 to about 30, from about 0.2 to about 5, from about 0.5 to about 3.5, or from about 1 to about 2.5. For example, the aspect ratio of the nanostructure may be within this range.

The instrument surface may comprise a single pattern, as shown in FIG. 4, or may include multiple repetitions of the same or different patterns. For example, FIG. 5 illustrates a surface pattern that includes multiple repeated patterns of FIG. 4 on a surface.

The formation of nanotopography on the surface can increase the surface area without an increase in the corresponding volume. It is believed that increasing the ratio of surface area to volume increases the interaction between the surface and the surrounding biological material. For example, it is believed that increasing the ratio of surface area to volume increases the mechanical interaction between nanotopography and surrounding proteins, e. G., Extracellular matrix (ECM) proteins and / or plasma membrane proteins.

Generally, the ratio of surface area to volume of the device may be greater than about 10,000 cm ^-1 , greater than about 150,000 cm ^-1 , or greater than about 750,000 cm ^-1 . The determination of the ratio of surface area to volume can be performed according to any standard methodology as known in the art. For example, the specific surface area of a surface is generally determined by the method described in Brunauer, Emmet, and Teller (J. Amer. Chem. Soc., Vol. 60, Feb., 1938, (BET method) using nitrogen as the adsorbing gas as described for example in US Pat. No. 5,309,319, the BET surface area is less than about 5 m2 / g, in one embodiment, G to about 4.5 m < 2 > / g, or from about 0.5 m < 2 > / g to about 3.5 m < 2 > / g for surface area and volume. For example, the volume can be estimated from the calculated volume of each pattern element and the total number of pattern elements in a given area, for example on the surface of a single microneedle, depending on the geometry of the mold used. Lt; / RTI >

In the case of a device that confines complex pattern nano topography at the surface, nanotopography can be characterized through the determination of the fractal dimension of the pattern. The fractal dimension is a statistic that indicates how fully the fractal appears to fill the space as the cyclic iteration continues to a scaled-down scale. The fractal dimension of the two-dimensional structure can be expressed as:

Where N (e) is the number of self-similar structures needed to cover the entire object when the object is reduced by 1 / e in each spatial direction.

For example, considering the two-dimensional fractal known as the Sierpinski triangle shown in FIG. 6 where the midpoints of the three sides of the equilateral triangle are connected and the resulting inner triangle is removed, the fractal dimension is calculated as :

Thus, the Sierpinski triangle fractal represents an increased line length over the initial two-dimensional equilateral triangle. Also, this increase in line length does not involve a corresponding increase in area.

The fractal dimension of the pattern shown in FIG. 4 is about 1.84. In one embodiment, the nanotopography of the surface of the device may exhibit a fractal dimension of greater than about 1, for example from about 1.2 to about 5, from about 1.5 to about 3, or from about 1.5 to about 2.5.

Figures 7a and 7b show images of a large magnification of another example of composite nano topography. The nanotopographies of Figures 7a and 7b include an array of fiber-like fillers 70 located on a substrate. At the distal end of each individual pillar, the pillars are split into a plurality of smaller fibers 60. At the distal end of each such smaller fiber 60, each fiber is again split into a plurality of filaments (not visible in FIGS. 7A and 7B). The structure formed on the surface, having an aspect ratio of greater than about 1, may be flexible, such as the structures shown in Figs. 7A and 7B, or may be rigid.

Figures 7C and 7D show another example of composite nano topography. In this embodiment, a plurality of pillars 72 are formed on the substrate, each including an annular hollow 71 through the pillars. At the distal end of each hollow pillar, a number of smaller pillars 62 are formed. As can be ascertained, the pillars of Figures 7c and 7d maintain their rigidity and upright orientation. Additionally, in contrast to the previous pattern, the smaller pillar 62 of this embodiment has a different shape than the larger pillar 72. Specifically, the smaller pillar 62 does not have a hollow and is hollow. Thus, nanotopography, including structures formed with different scales, need not all have structures that are formed in the same shape, and structures may be different in both size and shape from structures of different scales.

Figure 8 shows another pattern comprising a nano-sized structure as may be formed on the instrument surface. As can be appreciated, in this embodiment, the individual pattern structures may be formed with the same general size, but with different orientations and shapes.

In addition to or instead of the above-mentioned methods, the surface can be characterized by other methods including, but not limited to, surface roughness, modulus of elasticity, and surface energy.

Methods for determining surface roughness are generally known in the art. For example, an atomic force microscope process in contact or non-contact mode can be used in accordance with standard work to determine the surface roughness of a material. The surface roughness that can be used to characterize the micro needle can include average roughness (R _A ), root mean square roughness, skewness, and / or kurtosis. Generally, the average surface roughness (i.e., the arithmetic mean height of the surface is the roughness parameter as defined in the ISO 25178 series) of the surface defining the nanotopography fabricated on the surface is less than about 200 nanometers, about 190 nanometers Less than about 100 nanometers, or less than about 50 nanometers. For example, the average surface roughness may be from about 10 nanometers to about 200 nanometers, or from about 50 nanometers to about 190 nanometers.

The instrument can be characterized by a change in the modulus of the nanopatterned surface, for example, when the nanotopography is added to the surface. In general, the addition of a number of structures forming nanotopography on the surface can reduce the modulus of elasticity of the material because, when a nano-sized structure is added onto the surface, the decrease in surface continuity and the change in surface area associated therewith Will result. Except for the pattern of nanotopography on the surface, the mechanism comprising nano-topography on the surface, compared to a similar surface formed with the same material according to the same process, is about 35% to about 99%, for example about 50% To about 99%, or from about 75% to about 80%. For example, the effective compressive modulus of elasticity of the nanopatterned surface may be less than about 50 MPa, or less than about 20 MPa. In one embodiment, the effective compressive modulus can be from about 0.2 MPa to about 50 MPa, from about 5 MPa to about 35 MPa, or from about 10 MPa to about 20 MPa. The effective shear modulus may be less than about 320 MPa, or about 220 MPa. For example, the effective shear modulus may be from about 4 MPa to about 320 MPa, or in one embodiment from about 50 MPa to about 250 MPa.

A mechanism that includes nano topography on a mechanism may exhibit an increase in surface energy relative to similar microneedles that do not have a surface that defines a pattern of nanotopography on the surface. For example, microneedles comprising nano-topography formed on a surface may have an increase in surface energy compared to similar microneedles formed of the same material and formed according to the same method but not including a pattern of nanotopography on the surface . For example, the water contact angle of the surface comprising nanotopography on the surface may be greater than about 80, greater than about 90, greater than about 100, or greater than about 110. For example, the water contact angle of the surface can be from about 80 DEG to about 150 DEG, from about 90 DEG to about 130 DEG, or in one embodiment from about 100 DEG to about 120 DEG.

When the nanostructure is formed on the surface of the device, packing density of the structure can be maximized. For example, elements may be patterned on a substrate using a square packing (e.g., 9a), a hexagonal packing (Figure 9b), or some modification thereof. When the elements of various sizes of cross-sectional areas A, B, and C design patterns adjacent to each other on the substrate, a one-pack packing as shown in Figure 9C can be used. Those of skill in the art will, of course, perform well in determining changes in pack density and associated surface properties.

A mechanism including nano topography fabricated on the surface of the device can be formed according to a one-step process. Alternatively, a multi-step process can be used to fabricate a pattern of nanostructures on a pre-formed surface. For example, it is possible first to form an array of micro-needles and then to create an irregular or regular pattern of nanostructures on the surface of the formed micro-needles. In a one-step or two-step process, the structure may be subjected to any suitable nanotopography fabrication method, including, but not limited to, nanoimprinting, injection molding, lithography, embossing, Can be produced.

Generally, an array of microneedles is used for lithography; Etching techniques such as wet chemical, dry, and photoresist removal; Thermal oxidation of silicon; Electroplating and electroless plating; Diffusion processes such as boron, phosphorus, arsenic, and antimony diffusion; Ion implantation; Film deposition such as evaporation (filament, electron beam, flash, and deposition and step coverage), sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam) May be formed according to any standard microfabrication technique including but not limited to plating, screen printing, lamination, stereolithography, laser machining, and laser ablation (including projection ablation).

Lithographic techniques, including photolithography, electron beam lithography, X-ray lithography, and the like, can be used to define key patterns and form a master die. Cloning can then be performed to form a device including an array of micro needles. Conventional replication methods include, but are not limited to, solvent-assisted microforming and casting, embossing, injection molding, and the like. Self-assembling techniques, including phase-separated block copolymers, polymer solution blending and colloidal lithography techniques, can also be used to form nano topography on the surface.

As is known, the methods can be used in combination. For example, a substrate patterned with a colloid can be exposed to reactive ion etching (RIE, also known as dry etching) to modify the properties of fabricated nanostructures such as nanofiller diameter, profile, height, pitch, . Wet etching may also be used to produce alternative profiles of the fabricated nanostructures that were initially formed according to different processes, e. G., Polymeric solution blending techniques. The structure diameter, shape and pitch can be controlled through the selection of suitable materials and methods.

Other methods as may be used to form microneedles comprising nanotopography fabricated on a surface are described in U.S. Patent No. 6,995,336 to Hunt et al., Which is incorporated herein by reference, and Guo, Lt; RTI ID = 0.0 > U.S. Patent No. 7,374,864, < / RTI > et al. Nanoimprint lithography is a nano-scale lithography technique that uses a hybrid mold frame that acts as both a nanoimprint lithography mold and a photolithography mask. A schematic diagram of a nanoimprint lithography technique is shown in Figs. 10a to 10c. During fabrication, the hybrid mold frame 30 imprintes in the substrate 32 through the applied pressure to form features (e.g., micro-needles that define nanotopography) on the resist layer (Fig. 10A). Generally the surface of the base material 32 can be heated to a temperature above its glass transition temperature (T _g) before engagement with the forming die 30. While the hybrid mold frame 30 is engaged with the substrate 32, the viscous polymer milk can be forced into the mold cavity to form the features 34 (Fig. 10B). Subsequently, the forming mold and the substrate may be exposed to ultraviolet light. Hybrid molds are generally transmissive to ultraviolet radiation except for certain areas that are obscured. Thus, ultraviolet light passes through the transmissive region into the resist layer. The pressure is maintained while the mold and the substrate are cooled. It is then removed from the substrate and the polymer T _g than the base material 32 of the hybrid cooling the molding die 30 at a low temperature (Fig. 10c).

10C, in order to facilitate the release of the nanoimprinted substrate 32 comprising the fabricated features 34 from the mold 30, the mold 30 is coated with a low energy coating It is advantageous to treat and reduce adhesion to the substrate 32 because the lower surface energy of the mold 30 and the resulting greater difference in surface energy between the mold 30 and the substrate 32 and the polymer Because the separation between the substances can be facilitated. For example, a silicon mold frame coating such as trideca- (1,1,2,2-tetrahydro) -octytrichlorosilane (F ₁₃ -TCS) can be used.

The structure may be formed according to a chemical addition process. For example, film deposition, sputtering, chemical vapor deposition (CVD); Structures can be formed on the surface using epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, and the like. A self-assembled monolayer process as known in the art can be used to form a pattern of structures on a surface.

The surface of the transdermal delivery device can be further functionalized in order to improve its interaction with tissue or individual cells in use. For example, one or more biomolecules, such as polynucleotides, polypeptides, whole proteins, polysaccharides, etc., can be conjugated to a pre-used structured surface.

In some embodiments, a surface comprising a structure formed on a surface may have a reactivity suitable to allow additional desired functionalities to spontaneously attach to the surface, without the need to pre-treat the surface. However, in other embodiments, the structured surface may be pretreated prior to attachment of the desired compound. For example, the reactivity of the structure surface can be enhanced by adding or generating an amine, a carboxylic acid, a hydroxy, an aldehyde, a thiol, or an ester group on the surface. In one exemplary embodiment, in order to increase the amine function of the surface and bind one or more biomolecules to the surface via the added amine functionality, the surface of the micro needle, including the pattern of nanostructures formed on the surface, With an amine-containing compound such as ethoxysilane.

Materials such as those that can preferably be bound to the surface of the patterned device may include ECM proteins such as laminin, tropoelastin or elastin, tropocollagen or collagen, fibronectin, and the like. Short polypeptide fragments such as the RGD sequence, which is part of the recognition sequence of integrins that bind to many ECM proteins, can be attached to the surface of the patterned instrument. Thus, functionalizing the microneedle surface using RGD can promote the interaction of the device with the ECM protein, and the foreign body reaction to the device during use can be further limited.

The transdermal delivery device may be in the form of a patch that may include various features. For example, the device may include a reservoir, e.g., a container, a porous matrix, etc., capable of storing the formulation and providing the formulation for delivery. The instrument may include a reservoir within the instrument itself. For example, the device may include a hollow, or a plurality of pores, which may be conveyed to deliver one or more agents. The formulation may be released from the device through dissolution of some or all of the device, or through diffusion of the formulation from the device.

11A and 11B are perspective views of a device including a reservoir. The instrument 110 includes a reservoir 112 defined by an impermeable backing layer 114 and a microneedle array 116. The backing layer and the micro needle array 116 are connected together near the outer boundary of the instrument, denoted 118. The impermeable backing layer 114 may be connected by adhesive, heat sealing, or the like. The instrument 110 also includes a plurality of micro needles 120. The release liner 122 may be removed to expose the micro needle 120 prior to use of the instrument.

Formulations containing one or more agents may be retained in reservoir 112. Materials suitable for use as the impermeable backing layer 114 may include materials such as polyester, polyethylene, polypropylene, and other synthetic polymers. The material may be sealed to the backing layer by heating or otherwise generally to provide a barrier against transverse flow of the reservoir contents.

The reservoir 112 defined by the space or gap between the impermeable backing layer 114 and the micro needle array 116 provides a storage structure that holds a suspension of the agent to be administered. The reservoir can be formed from a variety of materials compatible with the formulation contained therein. For example, natural and synthetic polymers, metals, ceramics, semiconductor materials, and composites thereof can form a reservoir.

In one embodiment, the reservoir can be attached to a substrate on which the microneedles are located. According to another embodiment, the reservoir may be separate and may be releasably connected to the microneedle array or in fluid communication with, for example, a suitable tubing, leur lock, or the like.

The device may include one or more reservoirs for storing the agent to be delivered. For example, the device may comprise a single reservoir for storing a single or multiple drug-containing formulations, or the device may comprise a plurality of reservoirs for storing one or more formulations for delivery to all or a portion of the array of micro- . ≪ / RTI > A plurality of reservoirs can store different materials, each of which can be combined for delivery. For example, the first reservoir may contain the agent, e.g., the drug, and the second reservoir may contain the vehicle, e.g., saline. The different agents may be mixed prior to delivery. Mixing may be triggered by any means, including, for example, mechanical disruption (i.e., perforation, degradation or rupture), alteration of porosity, or electrochemical decomposition of walls or membranes separating the chamber. A plurality of reservoirs may contain different active agents for delivery, which may be delivered together or sequentially.

In one embodiment, the reservoir may be in fluid communication with one or more of the microneedles of the transcutaneous device, and the microneedles may include a structure (e.g., a central or side bore) that allows the delivered formulation to be transported below the barrier layer Can be limited.

In an alternative embodiment, the instrument may comprise a micro needle assembly and a reservoir assembly, and the flow between the two is blocked prior to use. For example, the device may include an release member disposed adjacent to both the reservoir and the micro needle array. In use, the release member can be detached from the device prior to use so that the reservoir and the micro needle array are in fluid communication with each other. Separation can be carried out by partially or completely eliminating the release member. For example, in Figures 12-17, one embodiment of a release member configured to release from a transdermal patch to initiate flow of a drug compound is shown. More particularly, FIGS. 12-17 illustrate a transdermal patch 300 containing a drug delivery assembly 370 and a micro needle assembly 380. The drug delivery assembly 370 includes a reservoir 306 disposed adjacent to the flow rate regulating membrane 308.

The flow rate control membrane can assist in slowing its flow rate upon release of the drug compound. Specifically, fluid drug compounds that pass from the drug reservoir through the microfluidic channel to the microneedle assembly may experience a pressure drop that results in a slowing of the flow rate. If this difference is too great, there may be some backpressure that can interfere with the flow of the compound and potentially overcome the capillary pressure of the fluid through the microfluidic channel. Thus, the use of flow control membranes can allow such pressure differences to be mitigated and the drug compound to be introduced into the micro needle at a more controlled flow rate. The particular material, thickness, etc., of the flow rate control membrane may vary depending on many factors such as the viscosity of the drug compound, the desired delivery time, and the like.

Flow rate control membranes can be made from permeable, semipermeable or microporous materials having permeation enhancer permeability lower than drug reservoirs known in the art to control the flow rate of drug compounds. For example, the material used to form the flow rate control film may be from about 50 nanometers to about 5 micrometers, in some embodiments from about 100 nanometers to about 2 micrometers, in some embodiments from about 300 nanometers to about 1 micro And may have an average pore size of the meter (e.g., about 600 nanometers). Suitable film materials include, for example, fibrous webs (e.g., woven or nonwoven), apertured films, foams, sponges, etc., which may include polyethylene, polypropylene, polyvinylacetate, ethylene n-butyl acetate and ethylene Vinyl acetate copolymer. The membrane material is also described in U.S. Patent Nos. 3,797,494, 4,031,894, 4,201,211, 4,379,454, 4,436,741, 4,588,580, 4,615,699 In more detail in U.S. Patent Nos. 4,661,105, 4,681,584, 4,698,062, 4,725,272, 4,832,953, 4,908,027, 5,004,610, 5,310,559, 5,342,623, 5,344,656, 5,364,630 and 6,375,978 ≪ / RTI > Particularly suitable membrane materials are available from the Lohmann Therapie-Systeme.

12 and 13, the assembly 370, although optional, also includes an adhesive layer 304 disposed adjacent the reservoir 306. The microneedle assembly 380 also includes a support 312, from which a plurality of microneedles 330 with channels 331 extend, as described above. The layers of the drug delivery assembly 370 and / or the micro needle assembly 380 may be attached together as desired via any known bonding technique, such as adhesive bonding, thermal bonding, ultrasonic bonding, and the like.

Regardless of the particular configuration used, the patch 300 also contains a release member 310 disposed between the drug delivery assembly 370 and the micro needle assembly 380. The release member 310 may optionally be coupled to the adjacent support 312 and / or the flow rate regulating membrane 308, but typically the release member 310 may be easily detached from the patch 300, It is desirable to merely weakly bond. The release member 310 also includes a tab portion 371 at least partially extending beyond the border of the patch 300 to facilitate the user to grip the member and pull it in the desired direction ). ≪ / RTI > In the "inactive" configuration as shown in Figures 12 and 13, the drug delivery assembly 370 of the patch 300 is configured such that the drug compound 307 does not flow into the micro needle 330 to any significant extent The drug compound 307 is safely retained. The patch can be "actuated" simply by applying a force to the release member to release the release member from the patch.

In Figures 14 and 15, one embodiment of patch 300 operation is shown, which pulls release member 310 in a longitudinal direction. The entire release member 310 can be removed as shown in Figs. 16 and 17, or simply removed partially as shown in Figs. 14 and 15. However, in either case, the previously formed suture between the release member 310 and the opening (not shown) of the support 312 ruptures. In this manner, the drug compound 107 may begin to flow from the drug delivery assembly 170 into the channel 131 of the micro needle 130 through the support 112. Exemplary drawings showing how the drug compound 307 flows into the channel 331 from the reservoir 306 are shown in FIGS. 16 and 17. FIG. In particular, the flow of the drug compound 307 is passively initiated and does not require any active displacement mechanism (e.g., a pump).

In the embodiment shown in Figures 12-17, since the drug delivery assembly is already arranged in fluid communication with the micro needle assembly, the desorption of the release member immediately initiates the flow of the drug compound into the micro needle. However, in certain embodiments, it may be desirable to have the user more effectively control the time of release of the drug compound. This can be accomplished through the use of a patch configuration in which the micro needle assembly is initially in fluid communication with the drug delivery assembly. When the user wishes to use the patch, the user can physically manipulate the two separate assemblies in fluid communication. The release member can be separated before or after the physical operation is performed.

For example, in Figures 18-23, one particular embodiment of patch 200 is shown. Figures 18 and 19 illustrate a patch 200 prior to use and illustrate a second section 260 formed by a first section 250 formed by a micro needle assembly 280 and a drug delivery assembly 270. The drug delivery assembly 270 includes a reservoir 206 disposed adjacent the flow rate control membrane 208 as described above. Although optional, the assembly 270 also includes an adhesive layer 204 disposed adjacent the reservoir 206. The micro needle assembly 280 also includes a support 212, from which a plurality of micro needles 230 with channels 231 extend, as described above.

In this embodiment, the support 212 and the flow rate regulating film 208 are initially disposed horizontally adjacent to each other and the release member 210 extends on the support 212 and the flow rate regulating member 208 . In this particular embodiment, the release member 210 is preferably releasably attached to the support 212 and the flow rate regulating film 208 by an adhesive (e.g., a pressure sensitive adhesive). 18 and 19, the drug delivery assembly 270 of the patch 200 is configured to dispense the drug compound 207 ). The release member 210 is peeled away as shown in FIGS. 20 and 21 to form a gap between the release member 210 and the opening (not shown) of the support 212, The formed suture portion can be ruptured. The second section 260 is then placed in a fold line "F" as shown by the directional arrow in Figure 22 so that the flow rate regulating member 208 is disposed adjacent and perpendicularly to the support 212 Can be folded. Alternatively, the first section 250 may be folded. In either case, folding the section 250 and / or section 260 causes the drug compound 207 to flow from the drug delivery assembly 270 through the support 212 into the channel 231 of the micro needle 230 (See Fig. 23).

The device can deliver the formulation at a therapeutically useful rate. To this end, the transdermal device may include a housing with microelectronic and other microfabricated structures that adjust the delivery rate by a patient, a medical professional or a biosensor, according to a pre-programmed schedule or via a dynamic interface . The device may include a substance on the surface having a predetermined rate of degradation to control the release of the formulation contained within the device. The rate of delivery, the properties of the delivered formulation (e.g., viscosity, charge and / or chemical composition); The dimensions of each instrument (e.g., the outer diameter and volume of any opening); The number of micro needles on the transdermal patch; The number of individual instruments in the carrier matrix; Application of thrust (for example, concentration gradient, voltage gradient, pressure gradient); The use of valves, and the like.

The delivery of the agent through the device can be controlled or monitored using various combinations of valves, pumps, sensors, actuators and microprocessors, for example. These components can be prepared using standard fabrication or microfabrication techniques. Actuators that may be useful in a device may include a micropump, a microvalve, and a positioner. For example, the microprocessor may be programmed to regulate the pump or valve, thereby regulating the delivery rate.

The flow of the formulation through the device may occur based on diffusion or capillary action, or may be induced through conventional mechanical pumps or non-mechanical propulsive forces, such as electroosmosis or electrophoresis, or convection. For example, in electroosmosis, an electrode may be placed on a biological surface (e.g., a skin surface), a microneedle, and / or a substrate adjacent to the microneedles to transfer the opposite charged ionic species and / Thereby creating a convective flow that is directed toward the site or to the delivery site.

The flow of the formulation can be manipulated through the selection of the material forming the micro needle surface. For example, one or more large grooves adjacent to the microneedle surface of the instrument may be used to guide the passage of drug, especially in the liquid state. Alternatively, the physical surface properties of the device can be manipulated to facilitate or inhibit material transport along the surface, such as by controlling hydrophilicity or hydrophobicity.

The flow of the formulation can be controlled using valves or gates as are known in the art. The valve may be repeatedly opened and closed, or the valve may be a disposable valve. For example, a frangible barrier or a one-way gate can be installed in the device between the reservoir and the patterned surface. When ready for use, the barrier can be ruptured or the gate can be opened to allow flow to the surface of the micro needle. Other valves or gates used in the instrument may be operated thermally, electrochemically, mechanically, or magnetically to selectively initiate, modulate, or interrupt the flow of molecules through the instrument. In one embodiment, the flow is regulated by using a flow rate limiting membrane as a "valve. &Quot;

In general, any formulation delivery control system, including reservoirs, flow control systems, sensing systems, etc., as known in the art, may be introduced into the apparatus. For example, U.S. Patent Nos. 7,250,037, 7,315,758, 7,429,258, 7,582,069, and 7,611,481 disclose storage and conditioning systems as can be introduced into the apparatus.

The subject matter of the patent will be better understood with reference to the embodiments set forth below.

≪ Example 1 >

A number of different molds were fabricated using photolithography techniques similar to those used in the design and manufacture of electrical circuits. Individual process steps are generally known and described in the art.

First, the silicon substrate was cleaned with acetone, methanol and isopropyl alcohol, and then coated by a chemical vapor deposition process with a 258 nanometer (nm) silicon dioxide layer.

The JEOL JBX-9300FS EBL system was then used to form a pattern on each substrate through an electron beam lithographic patterning process as is known in the art. The process conditions were as follows:

Beam current = 11 nA

Acceleration voltage = 100 kV

Shot pitch = 14 nm

Dose = 260 μC / cm 2

Resist = ZEP520A, thickness of about 330 nm

Developer = n-amyl acetate

Development = rinsing with isopropyl alcohol for 30 seconds after immersion for 2 minutes.

Silicon dioxide etching was then performed via STS Advanced Oxide Etch (AOE). 55 sccm (standard cubic centimeters per minute) He, 22 sccm CF ₄ and 20 sccm C ₄ F ₈ were used at a DC bias of 4 mTorr, 400 W coil, 200 W RIE and 404-411 V, and the etching time was 50 seconds .

Silicon etching was then performed via STS silicon oxide etching (SOE). 20 sccm Cl ₂ and 5 sccm Ar were used at a DC bias of 5 mTorr, 600 W coil, 50 W RIE and 96-102 V, and the etching time was 2 minutes. The silicon etch depth was 500 nanometers.

Removal of residual oxides, including deionized water rinsing, was performed using a buffered oxide etch reagent (BOE) after 3 minutes BOE immersion.

Obducat Nil-Eiter® 6 nanoimprinter was used to form nanopatterns on various polymeric substrates. Water supplied from outside was used as cooling water. The UV module used a single pulse lamp with a wavelength of 200 to 1000 nanometers at 1.8 W / cm < 2 >. A UV filter of 250 to 400 nanometers was used. At a maximum temperature of 200 < 0 > C and 80 Bar, the exposed area was 6 inches. The nanoimprinter included a semi-automatic separation unit and a self-regulating deformation.

Was treated with trichloromethyl okti as silane (F ₁₃ -TCS) - Nano Im to the printing film can be easily release from the forming mold, the forming mold tree deca - (1,1,2,2-tetrahydro). To treat the mold, the silicon mold was first rinsed with a cleaning solution of acetone, methanol, and isopropyl alcohol, followed by drying with nitrogen gas. The petri dishes placed on a hot plate in a nitrogen atmosphere, was added 1 to 5 F ₁₃ -TCS ㎖ in a Petri dish. After laying the silicon mold for molding a Petri dish, the coating for 10 to 15 minutes by ₁₃ F -TCS steam to screen wet the silicon forming mold to remove the mold.

Five different polymers as given in Table 1 below were used to form various nanotopograph designs.

A number of different nanotopographical patterns have been formed, the schematic of which is shown in Figures 24a to 24d. The nano topography pattern shown in Fig. 24E was the surface of a flat substrate purchased from NTT Advanced Technology, Tokyo, Japan. The pattern was designated as DN1 (Fig. 24A), DN2 (Fig. 24B), DN3 (Fig. 24C), DN4 (Fig. 24D) and NTTAT2 (Fig. SEM images of the mold are shown in Figures 24A, 24B and 24C, and the images of the film are shown in Figures 24D and 24E. FIG. 8 shows a nanopatterned film formed by using the forming die DN1 of FIG. 24A. In this particular film, the polymeric features were induced by temperature changes as discussed above. The surface roughness of the pattern of Fig. 24E was found to be 34 nanometers.

The patterns shown in Figs. 7C and 7D were also formed according to the nanoimprinting process. This pattern included a filler 72 and a filler 62, as shown. The larger filler 72 was formed to have a diameter of 3.5 micrometers (占 퐉), a height of 30 占 퐉 and a center-to-center spacing of 6.8 占 퐉. The filler 62 was 500 nanometers in height, 200 nanometers in diameter, and 250 nanometers in center-to-center spacing.

The nanoimprinting process conditions used in the polypropylene film are provided in Table 2 below.

≪ Example 2 >

A film comprising various different patterns and formed of polystyrene (PS) or polypropylene (PP) was formed as described in Example 1 above. The lower substrate had various thicknesses. The pattern used was DN2, DN3, or DN4 using the formation process as described in Example 1. The patterning molds varied in hole depth and feature spacing to form variously sized features with a specified pattern. 8 samples (designated BB1) were formed using a 0.6 micron millipore polycarbonate filter as a mold. A 25 탆 polypropylene film was placed on the filter, followed by hot melting to allow polypropylene to flow into the pores of the filter. The mold was then cooled and the polycarbonate mold was melted using a methylene chloride solvent.

The SEM of the formed film is shown in Figures 25 to 33 and the properties of the formed film are summarized in Table 3 below.

For each sample, the film was characterized using AFM. Characterization included the creation of a scanning electron microscope (SEM), determination of surface roughness, determination of maximum feature height measurements, and determination of fractal dimensions.

The atomic force microscope (AFM) probe used was a series 16 silicon probe and a cantilever available from MASCH. The cantilever had a resonance frequency of 170 kHz, a spring constant of 40 N / m, a length of 230 5 m, a width of 40 3 m, and a thickness of 7.0 0.5 m. The tip of the probe has an n-type doping with a typical probe tip radius of 10 nanometers, a tip cone full angle of 40 degrees, a tip total height of 20 to 25 micrometers, and a bulk resistivity of 0.01 to 0.05 ohm-cm Lt; / RTI >

The surface roughness values given in Table 4 are the arithmetic mean heights of the surface area roughness parameters as defined in ISO 25178 series.

Fractal dimensions were calculated by analyzing the Fourier amplitude spectrum for different angles; The amplitude Fourier profiles were obtained for different angles and the algebraic coordinates of frequency and amplitude were calculated. Then for each direction, the fractal dimension D is calculated as:

D = (6 + s) / 2

Where s is the (negative) slope of the log-log curve. The recorded fractal dimension is the average for all directions.

Fractal dimensions can also be evaluated from a 2D Fourier spectrum by applying a log-log function. If the surface is a fractal, the log-log graph should be nearly linear with a negative slope (see, for example, Fractal Surfaces, John C. Russ, Springer-Verlag New York, LLC, July, 2008).

≪ Example 3 >

To form an array of microneedles containing nanopatterned surfaces. First, an array of microneedles as shown in Fig. 2 was formed on a silicon wafer through a photolithography process. Each needle included two opposite side channels (not shown in FIG. 2) positioned opposite each other, aligned through one through-die hole at the base of the needle.

Microneedles were formed on silicon-based wafers following a typical microfabrication process. (Oxide etching, DRIE etching, iso etching), resist stripping, oxide stripping, and lithography techniques (e.g., isolithography, hole lithography, and lithography) are performed according to standard methods after laminating resist and / Slit lithography) was performed to form an array of microneedles.

After forming the microneedle array, a 5 탆 polypropylene film containing the DN2 pattern formed as described in Example 1 above, having the characteristics described in Sample 2 in Table 4, was placed on the microneedle array. The wafer / film structure was held in a heated vacuum box (3 inches H ₂ O vacuum) at elevated temperature (130 ° C) for 1 hour to gently pull the film onto the microneedle surface while maintaining the nanopatterned surface of the film.

Figures 34A-34D illustrate a film on a microneedle array of large magnification.

Although the subject matter of the patent has been described in detail with regard to specific embodiments thereof, those skilled in the art will readily appreciate that alternatives, modifications, and equivalents of such embodiments may be devised, provided that those skilled in the art understand the above. Accordingly, the scope of the present disclosure should be defined as the scope of the appended claims and any equivalents thereof.

Claims (17)

A plurality of nanostructures fabricated on the surfaces of the micro needles and the micro needles, arranged in a predetermined pattern; And
A composition comprising a bioactive agent and having a viscosity of greater than about 5 centipoise, for example, from about 10 centipoise to about 50 centipoise,
A delivery mechanism for delivering the bioactive agent across the skin barrier. The apparatus of claim 1, wherein the composition comprises a bioactive agent at a concentration of greater than about 5 mg / ml, such as from about 35 mg / ml to about 500 mg / ml. 3. The device of claim 1 or 2, wherein the bioactive agent has a molecular weight of greater than about 100 kDa. 4. The device according to any one of claims 1 to 3, wherein the bioactive agent is a protein therapeutic. 5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is a pharmaceutically acceptable excipient selected from the group consisting of one or more pharmaceutically acceptable excipients such as solvents, penetration enhancers, thickeners, wetting agents, lubricants, A device further comprising an excipient. 6. The apparatus according to any one of claims 1 to 5, wherein the pattern further comprises a microstructure, wherein the nanostructure has a smaller cross-sectional dimension than the cross-sectional dimension of the microstructure. The apparatus of claim 6, wherein the microstructure has a cross-sectional dimension of greater than about 500 nanometers, and the nanostructure has a cross-sectional dimension of less than about 300 nanometers. The apparatus of claim 6 or 7, further comprising a second nanostructure having a cross-sectional dimension that is less than the cross-sectional dimension of the microstructure and that is greater than the cross-sectional dimension of the first nanostructure. The apparatus of claim 1, wherein at least a portion of the nanostructure has one or more of the following characteristics:
a) a center-to-center spacing of from about 50 nanometers to about 1 micrometer,
b) a height of from about 10 nanometers to about 20 micrometers,
c) an aspect ratio of from about 0.15 to about 30; 10. The instrument of any one of claims 1 to 9, wherein the pattern has a fractal dimension greater than about one. 11. The method of any one of claims 1 to 10, wherein the microneedle surface comprising a plurality of nanostructures has an average surface roughness of about 10 nanometers to about 200 nanometers and / or an effective value of about 4 MPa to about 320 MPa Mechanisms with compressive modulus. Penetrate the stratum corneum of a subject using a micro needle of the device of any one of claims 1 to 11;
The composition is delivered through the micro needles at a rate of about 0.4 mg / hr / cm < 2 > based on the surface area of the micro needles
Wherein the bioactive agent is administered to a subject. 13. The method of claim 12, wherein the stratum corneum is a layer of skin of the subject, the skin comprises tight junctions between the cells of the skin, and the nanostructure enhances the porosity of the skin by rearranging the close- Way. 14. The method according to claim 13, wherein the rearrangement of the tight junction results in the enhancement of the porosity of a second tissue type, e.g., vascular tissue, that is not in contact with the microneedles. Penetrate the stratum corneum of a subject using a micro needle of the device of any one of claims 1 to 11;
The composition is delivered through the micro needles at a rate of about 0.4 mg / hr / cm < 2 > based on the surface area of the micro needles
Wherein the bioactive agent is administered to a subject. 16. The method of claim 15, wherein the stratum corneum is a layer of skin of the subject, the skin comprises tight junctions between cells of the skin, and the nanostructure enhances the porosity of the skin by rearranging the close- Way. 17. The method of claim 16, wherein rearrangement of the tight junction results in enhanced porosity of a second tissue type, e.g., vascular tissue, that is not in contact with the microneedles.

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